Newsletter Xagena

New data from the core and extension phases of the DRIVE PK phase 2 study of Mitapivat ( AG-348 ) in adults with pyruvate kinase ( PK ) deficiency were published in the New England Journal of Medicine ( NEJM ).
Mitapivat is an investigational, first-in-class, oral, small molecule allosteric activator of wild-type and a variety of mutated pyruvate kinase-R ( PKR ) enzymes that directly targets the underlying metabolic defect in PK deficiency, a rare, potentially debilitating, hemolytic anemia.

The DRIVE PK study is the first clinical trial in adults with PK deficiency.Data from the study have demonstrated rapid, clinically significant increases in hemoglobin in 50% of patients, and for patients in the extension phase, the response was sustained for up to 35 months.

There are no approved therapies for PK deficiency, and there are significant risks associated with current disease management strategies.
By directly targeting the underlying metabolic defect in PK deficiency, Mitapivat has the potential to be the first disease-altering therapy for these patients.

Data from the extension phase of the DRIVE PK study have shown that patients who respond to long-term treatment with Mitapivat had continued evidence of decreased hemolysis as demonstrated by directionally appropriate changes over time in hemoglobin, absolute reticulocyte counts, indirect bilirubin, haptoglobin and lactate dehydrogenase.

DRIVE PK is an ongoing global, open-label, phase 2, safety and efficacy study evaluating Mitapivat in adults with PK deficiency who do not receive regular transfusions.
Patients were randomly assigned to receive either 50 mg or 300 mg of Mitapivat twice daily for a 24-week core period and eligible patients could continue treatment in an ongoing extension phase.
As of the August 31, 2018 data cutoff, 52 patients were randomized and 43 ( 83% ) completed the core period.
Thirty-six ( 69% ) patients entered and 19 ( 37% ) remain in the extension phase with a median treatment duration of 28.9 months [ range 21.6-34.8 ].
The median baseline hemoglobin was 8.9 g/dL ( range, 6.5–12.3 g/dL ).
Nearly half ( 48% ) of the patients has reported a history of treatment with iron chelation despite the absence of regular transfusions, while the majority of patients had a prior splenectomy ( 83% ) and cholecystectomy ( 73% ).

A safety analysis conducted for all 52 treated patients as of the data cut-off has shown that adverse events associated with Mitapivat were mainly low-grade and transient.
The cumulative safety profile ( core plus extension phase ) remained similar to that observed in the core period and continues to support long-term twice daily dosing.
The majority of adverse events were grade 1-2; the most frequent were headache ( 46% ), insomnia ( 42% ) and nausea ( 40% ).
These events resolved within seven days after the initiation of treatment in 92% of episodes of headache, 47% of episodes of insomnia, and 78% of episodes of nausea.
Nine patients experienced grade greater than or equal to 3 treatment-related adverse events: hypertriglyceridemia ( n=4 ), hemolytic anemia ( n=2 ) and hemolysis, dizziness, headache, left renal cell carcinoma and insomnia ( n=1 each ).
Changes from baseline in sex hormone levels were observed in men, the result of mild off-target aromatase inhibition, with most values of testosterone and estradiol remaining within the normal range.
Interpretation of sex hormone data in females was confounded by variability in menopausal status and hormonal contraception use and will be assessed further in the phase 3 studies.

In the efficacy analysis, 26 of 52 patients ( 50% ) achieved a clinically significant maximum hemoglobin increase of more than 1.0 g/dL in the Core Period with improvement in other markers of hemolysis as of the data cutoff.
In patients who had hemoglobin increases of more than 1.0 g/dL in the Core Period, the mean maximum hemoglobin increase was 3.4 g/dL ( range, 1.1–5.8 g/dL ).
The median time to first hemoglobin increase of more than1.0 g/dL was 10 days ( range 7–187 days ).
Twenty patients maintained a hemoglobin response more than1.0 g/dL for more than 50% of assessments in the Core Period.
The hemoglobin response was maintained in 19 patients who continued to be treated in the extension phase, all of whom had at least 21.6 months of treatment.
In the patients with a hemoglobin response, directionally appropriate changes over time in absolute reticulocytes counts, indirect bilirubin, haptoglobin and lactate dehydrogenase provide additional evidence of decreased hemolysis with Mitapivat treatment.

Pyruvate kinase deficiency is a rare, inherited disease that presents as chronic hemolytic anemia, which is the accelerated destruction of red blood cells.
The inherited mutations in PKR genes cause a deficit in cellular energy within the red blood cell, as evidenced by lower PK enzyme activity, a decline in adenosine triphosphate levels and a build-up of upstream metabolites, including 2,3-DPG ( 2,3-diphosphoglycerate ).
PK deficiency is associated with serious complications including gallstones, pulmonary hypertension, extramedullary hematopoiesis, cirrhosis, osteoporosis, and iron overload and its sequelae, which occur regardless of the degree of anemia or transfusion burden.
Current management strategies for PK deficiency, including blood transfusion and splenectomy, are associated with both short- and long-term risks.

More than 300 different mutations have been identified to date. The mutations observed in PK deficiency patients are classified in two main categories.
A missense mutation causes a single amino acid change in the protein, generally resulting in some functional protein.
A non-missense mutation is any mutation other than a missense mutation, generally resulting in little functional protein.
It is estimated that 58% of patients with PK deficiency have two missense mutations, 27% have one missense and one non-missense mutation, and 15% have two non-missense mutations. ( Xagena )